6-alkanoylthio-4-en-3-oxo steroids and process for production thereof

ABSTRACT

Hormonal 6 Epsilon -lower alkanoylthio-3-oxo-4-en-steroids are prepared from corresponding 6 Epsilon -halo-3-oxo-delta-4steroids and 6 Epsilon -lower alkanoylthio-5-hydroxy-3-oxosteroids. They are also useful as intermediates for synthesis of hormonal thieno-(4&#39;&#39;,3&#39;&#39;,2&#39;&#39;-4,5,6,)steroids which have been disclosed in U.S. Pat. No. 3,300,485.

United States Patent [72] Inventor 211 App]. No.

[22] Filed [45] Patented [73] Assignee 32 Priority l Taichiro Komeno Osaka-shi, Japan 786,728

Dec. 24, 1968 Dec. 14, 1971 Shionogi & Co., Ltd. Osaka, Japan Apr. 3, 1962 Japan Continuation-impart of application Ser. No.

610,825, Jan. 23, 1967, now abandoned which is a division of application Ser. No. 335,662, Jan. 3, 1964, now Patent No. 3,300,485, which is a continuation-in-part of application Ser. No. 269,899, Apr. 2, 1963, now abandoned. This application Dec. 24, 1968, Ser. No. 786,728

[54] 6-ALKANOYLTHlO-4-EN-3-OXO STEROIDS AND PROCESS FOR PRODUCTION THEREOF [5 Claims, No Drawings Field of Search US. Cl Mil/239.55".

Int. Cl ..C07c 173/00,

C07c 169/20 lMachine Searched Steroids References Cited OTHER REFERENCES Chem Abstracts I964) Vol. 6 l Par. 10,749 relied on.

Primary Examiner Elbert L. Roberts Allorney-Wenderoth, Lind & Ponack 6-ALKANOYLTHlO-4-EN-3-OXO STEROIDS AND PROCESS FOR PRODUCTION THEREOF The present application is a continuation-in-part of application Ser. No. 610,825, filed Jan. 23, l967, now abandoned, which application is a division of application Ser. No. 335,662, filed Jan. 3, 1964, now US Pat. No. 3,300,485 which application is a continuation-in-part of application Ser. No. 269,899, filed Apr. 2, 1963, now abandoned.

The present invention relates to a novel process for preparing e-lower alkanoylthio-4-en-3-one steroids and the novel products thereof, which are useful as medicinals and as important intermediates for preparing useful novel hon'nones such as thieno[4', 3, 2'-4,5,6]steroids as stated in our US. Pat. No. 3,300,485.

The object of the present invention is to provide a novel 6:- lower alkanoylthio-4-en-3-one steroids. Another object of this invention is to provide a process for preparing them. The other object is to provide a useful medicine. The other object is to provide a convenient intermediates for production of useful thieno [4', 3', 2-4,5,6]steroids. These and other objects of the present invention will be apparent from the descriptions hereinafter presented.

The compounds of the present invention are 4-en-3-one steroids bearing a (Se-lower alkanoylthio substituent, represented by the partial formula:

E SAc (I) wherein Ac represents a lower alkanoyl group, which represents positions 3, 4, 5, 6 and 7 of the steroid molecule, especially of the androstane, estrane, pregnane and cholestane series. Various substituents such as hydroxyl, acyloxy, ether, oxo, formyl, ester, carboxyl, lactones, lower alkyl, lower alkenyl, lower alkynyl, amino, substituted amino, double bond, and the like may be present in the steroid skeleton and/or the side chain.

Of the compounds of the invention, those represented by the following formula: III,

- t R /\l/W a Z S-Ac wherein Ac represents a lower alkanoyl group; R is hydrogen or methyl group; R is hydroxyl group, OAc group or a l7-side chain of the pregnane or cholestane series, and R is hydrogen atom, hydroxyl group or ethynyl group; or when combined together, R and R represent an oxygen atom; Z is methylene group or carbonyl group, are important. Examples of acyl group represented by Ac include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, caproyl, tert-butylacetyl, cyclopentane-carbonyl, cyclohexanecarbonyl, enanthoyl, octanoyl, capryl, decanoyl, undecanoyl, lauryl, etc. A few example of the compounds of this invention includes: 6a-acetylthio-4-androstene-3, l 7-dione, 6B-acetylthio-4-androstene-3,l7-dione, 6aand 6B-propionylthio-4-androstene- 3,1 7-dione, 6aand 6fl-butyrylthio-4-androstene3, l 7-diones, 6a:- and 6B-valerylthio-4-androstene-3, l 7-diones, 6aand 6B- caproylthio-4-androstene-3, l 7-diones, 6a-acetylthio- 17/3- acetyloxy-4-androsten-3-one, 6B-acetylthiol 7 B-acetyloxy-4- androsten-3-one, 6aand ofl-propionylthio-l7B-acetyloxy-4- androsten-3-ones, 6aand 6B-propionylthio- 1 7B- propionyloxy-4-androsten-3-ones, 6aand 6B-acetylthio-I7B- hydroxy-4-androsten-3-ones and 6B-acetylthio-4J6-androstadien-3-one, 6aand 6B-propionylthio-l7B-hydroxy-4- androsten-B-ones and 601- and 6/3-butyrylthio-l7B-hydroxy-4- androsten-B-ones, 601- and GB-caproylthio-l7B-hydroxy-4-androsten-3-ones, 6aand 6B-acetyloxy-4-estren-3-ones, 601- 3,20-diones,

and fi-butyrylthio-l7B-acetyloxy-4-estren-3ones, 6aand ofl-valerylthio-l7/3-acetyloxy4-estren-3-ones, 6aand 6B- acetylthio-l7B-valeryloxy-4-estren-3-ones, 6aand 6B- acetylthio-17B-hydroxy-4-estren-3-ones and GB-acetylthio- 4,l6estradien-3-one, 601- and 6B-propionylthiol 7B-hydroxy- 4-estren-3-ones, 6aand 6B-acetylthio-l7B-acetyloxy-l7aethynyl-4-estren-3-ones, 601- and 6B-propionylthio-l7flacetyloxy-l7a-ethynyl-4-estren-3-ones, 6aand fl-propionylthio-l 7B-propionyloxyl 7a-ethynyl-4-estren-3-ones, 6aand 6B-acetylthiol 7B-caproyloxyl 7a-ethynyl-4-estren-3- ones, 60:- and 6fiacetylthio-l7B-hydroxy-l7a-ethynyl-4-estren-3-ones, 60:- and 6B-propionylthio-l7fl -hydroxy-l7aethynyl-4-estren-3-ones, 601- and 6B-acetylthio-4-pregnene- 604- and 6B-butyrylthio-4-pregnene-3,20- diones,6aand fi-acetylthiol 7a-hydroxy-4-pregnene-3 ,20- diones and 6B-acetylthio-4,l6-pregnadiene-3,20-dione, 6aand 6,8-propionylthio- 1 7a-hydroxy-4-pregnene-3 ,ZO-diones, 6aand fi-valerylthio-l7a-hydroxy-4-pregnene-3,20-diones, 6aand 6B-formylthio-4-cholesten-3-ones, 6aand 6/3- acetylthio-4-cholesten-3-ones, 6aand 6B-propionylthio-4- cholesten-3-ones, 6aand ofi-butyrylthio-4-cholesten-3-ones, 6aand 6B-valerylthio-4-cholesten-3-ones, 6aand 6B- caproylthio-4-cholesten-3-ones, 6aand 6B-acetylthio-17 01,2]-dihydroxy-4-pregnene-3,20-diones and ester and/or acetal derivatives thereof, 60:- and 6B-propionylthio-l7a,2ldihydroxy-4-pregnene-3,20-diones and ester and/or acetal derivatives thereof, 6aand 6B-acetylthio-l7a,2l-dihydroxy- 4-pregnene-3,l 1,20-trione and ester and/or acetal derivatives thereof, 60:- and 6/3-propionylthio-l7a,2l-dihydroxy-4- pregnene-3,l 1,20-trione and ester and/or acetal derivatives thereof and the like.

A process of the present invention comprises dehydration of 5a-hydroxy-3-oxo steroid bearing an 6e-lower alkanoylthio substituent, represented by the partial formula:

-Ac (Ill) wherein Ac represents the same significances as defined above, for the positions 3, 4, 5, 6 and 7 of the steroid molecule, especially of the androstane, estrane, pregnane and cholestane series. Various substituents such as hydroxyl, acyloxy, ether, oxo, forrnyl, ester, carboxyl, lactones. lower alkyl, lower alkenyl, lower alkynyl, amino, substituted amino,

double bond and the like may be present in the steroid skeleton and/or the side chain. A few of them may be changed in the reaction course, but they may be protected or recovered by the conventional manner in the art. important starting materials are illustrated by the following formula:

l 7B-acetyloxyandrostan-3-one, nylthiol 7,B-acetyloxyandrostan-3-one, a-hydroxy-6B- propionylthiol 7fl-propionyloxyandrostan-3-one, 50:, 17,8- dihydroxy-6B-acetylthioandrostan-S-one, 50:, l 'lB-dihydroxy- 6B-propionylthioandrostan-3-one, 5a, 1 7B-dihydroxy-6B-butyrylthioandrostan-ll-one, 5a, 1 7B-dihydroxy-6flcaproylthioandrostan-fl one, 5a-hydroxy-6B-acetylthiol 73- acetyloxyestran-B-one, 5a-hydroxy-6B-butyrylthio-17B- acetyloxyestran-3-one, Sa-hydroxy-B-valerylthio-17B- acetyloxyestran-Il-one, Sa-hydroxy-SB-acetylthiol 7,8- acetyloxyl 7a-ethynylestran-3-one, 5a-hydroxy-6B-propionylthiol 7B-acetyloxyl 7oz-ethynylestran-3-one, Sat-hydroxyofi-propionylthio-l7B-propionyloxy-17a-ethynylestran-3-one, 5a,17B-dihydroxy-GB-acetylthio-l7aethynylestran- 3-one, 5a, 1 7B-dihydroxy-6fl-propionylthiol 7a-ethynylestran-3- one, 5a-hydroxy-6,B-acetylthiopregnane-3,20-dione, 5ahydroxy-6B-propionylthiopregnane-3,ZO-dione, 5a-hydroxy-6 B-butyrylthiopregnane-S ,20-dione, 5a, 1 7a-dihydroxy-6flacetylthiopregnane-3,20-dione, 5a, 1 7a-dihydroxy-6B-propionylthiopregnane-3 ,20-dione, 511, l 7a-dihydroxy-6B- valerylthiopregnane-3,ZO-dione, 5a-hydroxy-6B- acetylthiocholestan-3-one, Sa-hydroxy-(SB-propionylthiocholestan-3-one, 5a-hydroxy-fi-butyrylthiocholestan- 3-one, 5a-hydroxy-6B-valerylthiocholestan-3-one and 5ahydroxy-6B-caproylthiocholestan-3-one. These starting materials, 5a-hydroxy-3-oxo steroids bearing a 6e-lower alkanoylthiosubstituent may be prepared from the corresponding 4-en-3-one steroids successively through the intermediates, 5-en-3-ketal steroids and 5a,6x-epoxy-3-one steroids by successive treatment with an alcohol such as ethylene glycol in the presence of an acid, a peroxide such as monoperphthalic acid and a lower alkanethiolic acid.

The reaction of this invention, the dehydration of the 5- hydroxyl group to form 4-double bond is accomplished by the action of an acid or an inorganic oxyacid halide in the presence of a base. In this reaction, when an acid is used as a reagent the corresponding 6a-alkanoylthio-4-en-3-one steroids are obtained as the product. On the contrary, when an inorganic oxyacid halide in the presence of a base is used as a reagent, the corresponding 6B-alkanoylthio-4-en-3-one steroids are obtained as the products. By further studies, it was confirmed that the later product, 6,8-epimer is very easily converted to the former product, but Ga-epimer transforms preferably in the presence of an acid. Therefore, the former product can also be synthesized by the successive treatment with an inorganic oxyacid halide in the presence of a base and with an acid. As for the acids to be used in the oa-epimer formation from the starting materials or from the ofl-epimers thereof, most organic and inorganic acids are generally applicable; e.g., hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, formic acid, tartaric acid and acetic acid. As the inorganic oxyacid halides, oxyacid halides of sulfur and phosphorous as thionyl halides and phosphoryl halides are applicable, wherein the ha- Sa-hydroxy-(SB-propiolides are the chloride, bromide or iodide. As the base to be used with the inorganic oxyacid halides, organic tertiary amines such as pyridine, trialkylamines such as trimethylamine and triethylamine, and dimethylaniline are applicable. The reaction with acid is performed in a solvent or in a mixture of several solvents, preferably of high dielectric constants, e.g., an organic acid such as acetic acid (glacial), an alkylated amide such as dimethylformamide or other polar solvents such as acetone, dioxane and tetrahydrofuran. The reaction may be completed in a short time, particularly within between several minutes to several hours, by the application of strong conditions such as the use dry hydrogen chloride in acetic acid or more slowly, particularly within 1 or 2 days by the use of a weaker acid. The reaction with the inorganic oxyacid halide in the presence of a base cited above proceeded much more quickly, and completes often within several minutes at a lower (about 0 C.) temperature. In the reaction with the inorganic oxyacid halide, the dehydration of the other hydroxyl group than Sat-hydroxyl is often observed, for exam- X wherein X represents a halogen atom, which represents positions 3, 4, 5, 6 and 7 of the steroid molecule, with a salt of thiolalkanoic acid. As for the halogen atom represented by X, chlorine, bromine and iodine are exemplified. Of the starting material of this process, a compound 0}: the formula:

wherein X represents a halogen atom; R, is hydrogen atom or methyl group; R is hydroxyl group, OAc group or a l7-side chain of the pregnane or cholestane series, and R is hydrogen, hydroxyl or an ethynyl; or when combined together, R, and R represent oxygen atom; Z is methylene group or carbonyl group, are important. Examples of the starting material of this process involve: 6a-iodo-4-androstene-3 l 7-dione, 6Biodo-4- androstene-3, l 7-dione, 6a-bromo-4-androstene-3, l 7-dione, 6B-bromo-4-androstene-3,l7-dione, 604- and 6B-chloro-4-androstene-3,l7-diones, 611- and GB-bromo-l7B-acetyloxy-4-androsten-3-ones, 6aand 6,8-iodo-l7B-propionyloxy-4-androsten-3-ones, 6aand 6B-bromo-l7/3-propionyloxy-4-androsten-3-ones, 6aand fl-bromo-l7/3-hydroxy-4-androsten- 3-ones, 6aand ofi-iodo-l7B-hydroxy-4-androsten-B-ones, 6aand 6/3-brom0-l7B-acetyloxy-4-estren-3-ones, 6aand 6/3-iodo-l7B-hydroxy-4-estren-3-ones, 601- and 6/3-bromo-l7 B-hydroxy-4-estren-3-ones, 6aand 6B-bromol7B-butyryloxy-4-estren-3-ones, 6aand fl-bromo-l7fi-caproyloxy-4-estren-3-ones, 601- and 6B-bromo-l7a-ethynyl-l7fl-hydroxy-4- androsten-3-ones, 6aand 6fl-iodol 7a-ethynyl-l 7B-hydroxy- 4-estren-3-ones, 6aand 6B-bromo-l7a-ethynyl-l 7/3- acetyloxy-4-estren-3-ones, 6a and 6B-iodo-4-pregnene-3,20- diones, 601- and 6B-bromo-4-pregnene-3,20-diones, 6aand 6B-bromo-l7a-hydroxy-4-pregnene-3,20-diones, 601- and 613- bromo-4-cholesten-3-ones, 601- and 6B-chloro-4-cholesten-3- ones, 60:- and fl-bromo-l7,2l-dihydroxy-4-pregnene-3,20- diones' and their ester and/or acetal derivatives, 6aand 6/3- bromo- 1 701,2 1 -dihydroxy-4-pregnene-3, l 1 ,20-triones and their ester and/or acetal derivatives, and the like.

The reaction of this process, the substitution of the 6- halogeno residue with acylthio group is accomplished by the action of a salt of alkanethiolic acid, preferably in the presence of solvent. The reaction may be carried out at cooled or elevated temperature. As for the alkanethiolic acid salts utilized in this process, there is exemplified by salts of thiolacetic acid, thiolformic acid, thiolpropionic acid, thiolbutyric acid, thiolvaleric acid, thiolisovaleric acid, thiolcaproic acid, thiolenanthoic acid, thiolcaproic acid and the like. The salts may be alkalimetal salts such as sodium, potassium, lithium salts or may be alkali earth salts such as magnesium or calcium salts or may be organic ammonium salts such as trimethylammonium salts, triethylammonium salts, etc. The preferable solvent includes dimethylformamide, acetone, acetonitrile, dimethylsulfoxide, tetrahydrofuran, dioxane and the like.

The compound of the present invention, especially those represented by the general formula 11 shows many remarkable hormone activities such as antiestrogenic high potency without other ill side effects (useful for therapeutics for uterine breeding, and so on, such as pituitary gonadotrophin inhibition activity), useful for controlling agents for diseases of menopause and for hypergonadism or precocious puberty, and useful for ovulation-inhibition agents or contraceptive agents. They are also useful as important and essential intermediates of thieno-[4', 3', 2'-4,5,61steroids bearing marked hormonal activities such as specific antiprogesteronic, antideciduomatogenic high potency useful for antifertilizing agent, which can be prepared by reaction of the products and a base. in the application of the products of the invention, both of the two epimers, 6e1- and 6/3'compounds, can be practically used as a medicine and as an intermediate.

The following examples are given to show the embodiment of the present invention. Many variations thereof may be possible without departing from the claims of the invention. Abbreviations are those conventional.

EXAMPLE 1 To a solution of 5a-hydroxy-6B-acetylthio-5a-androstane- 3,17-dione (2.00 g.) in pyridine (60 ml.), there is dropwise added thionyl chloride (1.00 g.) while cooling with a mixture of sodium chloride and ice, and the resultant mixture is stirred for 10 minutes under the same condition. After decomposition of excess of the reagent with ice, the reaction mixture is shaken with ether. The ether layer is separated, washed with water and dried. Afier removal of the solvent, the residue is crystallized from a mixture of acetone and hexane to give 65- acetylthio-4-androstene3,l7-dione (1.42 g.) as crystals melting at 170" to 171 C. [am-12988:? (rs-1.005, chloroform). UV-Spectrum: 237 mp. (e 15,820). lR-Spectrum: vggg 1,737, 1,689, 1,678, 1,617, 1,117 cmr. Anal; Calcd. for C H 8: C, 69.96; H, 7.83; S, 8.89. Found: C, 70.30; H, 7.97; S, 8.82.

The starting material of this example, a-hydroxy-6B- acetylthio-5a-androstane-3, 1 7-dione, is prepared from 5a,6a epoxy-5a-androstane-3,l7-dione [Campbell et al.: J. Am. Chem. Soc., Vol. 80, p. 4,717 (1958)] by treatment wi thiolacetic acid at room temperature.

EXAMPLE 2 10.55 g.) as a crude oil. IR-Spectrum: vg 'gg 1,736, 1.

EXAMPLE 3 5a-l-1ydroxy-6fl-acetylthio-5a-androstane-3 17-dione is reacted with thionyl chloride in pyridine as in example 1 whereby 6fi-acety1thio-4-androstene-3,17-dione is produced.

The product of this example (1.24 g.), glacial acetic acid (25 ml.) and p-toluenesulfonic acid monohydrate (0.21 g.) is allowed to stand at room temperature to 30 C.) for 48 hours. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dilute sodium carbonate solution and water in order and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue is chromatographed on activated magnesium silicate. The middle fraction eluted with petroleum ether-benzene is concentrated to give 601- acetylthio-4-androstene-3, l 7 dione (0.68 g.) as a crude oil.

EXAMPLE 4 To a solution of See-hydroxy-tifi-acetylthlo-l7fl-acetyloxy- Sa-androstan-il-one (6.53 g.) in pyridine (65 ml.), there is dropwise added thionyl chloride (4 ml.) while stirring at 0 C. After 5 minutes, the reaction mixture is poured into a mixture of ice and water and then shaken with chloroform. The chloroform layer is separated, washed with dilute hydrochlo' ric acid solution and water in order and dried. After removal of the solvent by evaporation, the residue (4.75 g.) is crystallized from a mixture of acetone and hexane to give crystals (2.55 g. The mother liquor of crystallization is concentrated and chromatographed on activated magnesium silicate. From the eluates with benzene and benzene-ether, there are obtained additional crystals (0.21 g.). The crystals are combined together and recrystallized from a mixture of ether and petroleum ether to give 6fl-acetylthio-l7fi-acetyloxy-4-androsten-3-one (2.59 g.) as pure crystals melting at 144 to 145 C. [011% 186,5:3:2 ($1.026, chloroform). UV-Spectrum: my 237 mp1 (6 15,960). [ll-Spectrum: 11" 1,740,

T58, 1,683, 1,614,1,243,1,132,1M6, 1,040 cm.- Anal.

EXAMPLE 5 To a solution of 5a-hydroxy-6B-acetylthio-17B-acetyloxy- 5a-androstan-3-one (1.00 g.) in glacial acetic acid (30 ml.) dry hydrogen chloride is passed through for 1 hour. The reaction mixture is combined with water and extracted with ether. The ether extract is washed with water and the solvent evaporated. The residue (0.93 g.) is chromatographed on activated magnesium silicate (30 g.). The fractions eluted with benzene and benzene-ether (9: 1-8:2) are combined together, concentrated and crystallized from methanol to give 6aacetylthio-l7fl-acetyloxy-4-androsten-3-one (0.50 g.) as crystals melting at 192 to 194 C. [a]"+40.3:2 (=l.016, chloroform). LIV- Spectrum: x3137 235 mp. (e 16,820). 1RSpectrum:\vfl .l,74l, l,687, l ,6l8, 1,244, 1,134, 1,044, 1,016 emf. Calcd. for C l-1 ,05: C, 68.28; H, 7.97; S, 7.93. Found: C, 68.39; H, 8.10, S, 7.89.

EXAMPLE 6 5a-1-1ydroxy-6fi-acetylthio- 17B-acetyloxy-5a-androstan-3- one is reacted with thionyl chloride in pyridine as in example 4 whereby 6B-acetylthio-l7B-acetyloxy-4-androsten-3-one is produced.

The product, 6/8-acetylthio-l7B-acetyloxy-4-androsten-3- one (2.76 g.) is dissolved in a mixture of p-toluenesulfonic acid monohydrate (0.60 g.) and glacial acetic acid (30 ml.) and the resultant solution is allowed to stand at room temperature 10 to 30 C.) for 48 hours. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water and dilute sodium carbonate solution in order and dried. After removal of the solvent by evaporation, the residue is chromatographed on activated magnesium silicate (60 g.). The fractions eluted with benzene and benzene-ether (9:1-4: 1) are combined together, concentrated and crystallized from methanol to give 6a-acetylthio-17 B-acetyloxy-4-androsten-3-one (1.15 g.) as crystals melting at 192 to 194 C.

EXAMPLE 7 To a solution of 5a-hydroxy-6B-acetylthio-5a-cholestan-3- one (1.44 g.) in pyridine (14 m1.) there is dropwise added thionyl chloride (0.70 ml.) at 0 C. while stirring. After 10 minutes, the reaction mixture is poured into a mixture of ice and water and shaken with a mixture of ether and benzene. The organic solvent layer is washed with water, dried and concentrated. The resultant 011 (1.15 g.) is crystallized from petroleum ether and recrystallized from methanol to give 63- Lamas; c. 75.93; H, 10.11; s, 6.99. Found c, 76.13; H,

EXAMPLE 8 To a solution of a-hydroxy-6B-acetylthio-5a-cholestan-3- one (0.32 g.) in glacial acetic acid (15 m1.) there is added ptoluenesulfonic acid monohydrate (0.10 g.), and the resultant mixture is allowed to stand at room temperature to 30 C.) overnight. The reaction mixture is combined with water and shaken with a mixture of ether and benzene. The organic solvent layer is washed with water and dilute sodium carbonate solution in order, dried and concentrated. The resultant oil is purified on chromatography with activated magnesium silicate whereby 6a-acety1thio4-cholesten-3-one (0.23 g.) is obtained as an oil. UV-Spectruin: km 235 u.

Cyclization of the product with alumitif'hffords 5- methylthienol4,3',2-4,5,6]-5-cholesten-3-one as crystals melting at 131 to 132 C.

EXAMPLE 9 5014-1ydroxy-6B-acety1thirr5a-cholestan-3-one is reacted with thionyl chloride in pyridine as in example 8 whereby 6B- tivated magnesium silicate for purification to give 61:-

acety1thio-4-cho1esten-3-one (0.08 g.) as an oil.

EXAMPLE 10 To a solution of 5a-hydroxy-6B-acetylthio-Sat-pregnanc- 3,20-dione (2.00 g.) in pyridine (20 m1.) there is dropwise added thionyl chloride (1 ml.) and the resultant mixture is stirred for 5 minutes at 0 C. The reaction mixture is poured into a mixture of ice and water and shaken with chloroform. The organic solvent layer is washed with water, dried and concentrated to dryness. The residue is crystallized from methanol to give 6B-acetylthio4pregnene'3,20-dione (1.25 g.) as crystals melting at 185 to 187 C. lal+243zt2 1.060, chloroform). UY-Spectrurn: Am 238 mp. (e 15,140). m-s eetrum fflm asmsssnesofrm 1, 1118 cm". Anal. Calcd. for C H O S: C, 71.0 9111, 8.30; S, 8.25. Found: C, 71.54; H, 8.46; S, 8.07.

EXAMPLE 11 To a solution of 5a-hydroxy-6B-acetylthio-5sit-pregnanc- 3,20-dione (0.30 g.) in glacial acetic acid (15 m1.) dry hydrogen chloride is passed through for 1 hour. The resulting mixture is allowed to stand at room temperature (10 to 30 C.) overnight. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dilute sodium carbonate solution and water in order, dried and concentrated to give 6a-acetylthio-4- pregnene-3,20-dione (0.24 g.) as a crude oil. UVHSpectrum: Am 236 [.t.

Cyc1ization of the product with alumina affords corresponding thienopregnene compound melting at 163 to 164 C.

EXAMPLE 12 5a-Hydroxy-6B-acetylthio-5wpregnane-3,20-dione is reacted with thionyl chloride in pyridine as in example 11 whereby 6B-acetylthio-4-pregnene-3,20-dione is produced.

To a solution of the product, 6fi-acetylthio-4-pregnene- 3,20-dione( 1.02 g.) in glacial acetic acid (30 m1.) dry hydrogen chloride is passed through for 30 minutes. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dilute sodium carbonate solution and water, dried and concentrated to give 6a-acetylthio-4-pregnene-3,20-dione (0.88 g.) as an oil.

EXAMPLE 13 To a solution of 501,17a-dihydroxy-6fl-acetylthio-5o1- pregnane-3,20-dione (0.83 g.) in glacial acetic acid (15 ml.) dry hydrogen chloride is passed through for 20 minutes while cooling with ice, and the resultant mixture is allowed to stand for 10 minutes under the same condition. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dilute sodium carbonate solution and water in order, dried over anhydrous sodium sulfate and concentrated to dryness to give 6a-acety1thio-17ahydroxy-4-pregnene-3,20-dione (0.81 g.) as an oil.

The product is cycllzed with sodium ethoxide to afford methy1thieno[4'l""',2-4,5,6]-5-pregnene-3,20-dione melting at 240 to 242 C.

The starting material of this example, 5a,17a-dihydroxy- 6B-acety1thio-5a-pregnane-3,20-dione, is prepared from 3,3:20,20-bisethy1enedioxy-Sa,6a-epoxy- 1 7a-hydroxy-5 apregnane [Babcock et al.: J. Am. Chem. Soc., Vol. 80, p. 2,904 (1958)] by treatment with thiolacetic acid at room temperature followed by refluxing with acetic acid.

EXAMPLE 14 To a solution of 511,17B-dihydroxy-6B-acety1thio17a-ethynyl-Sa-estran-3-one (0.33 g.) in glacial acetic acid (10 ml.) there is passed through dry hydrogen chloride for 2 hours. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dilute sodium carbonate solution and water in order, dried over anhydrous sodium sulfate and evaporated to dryness to give 6aacety1thio-17B-hydroxy-l7oz-ethyn l-4-estren-3-one (0.3 1 g.) as an oil. 1R-s eaa=z%%-3,4oo ,27s,i1,715, 1,683, 1,618, 1,130 cm"; 53, 3,626, 3,286, 1,700, 1,687, 1,622, 1,130 emf. w

The starting material of this example, 5a,17fi-dihydroxy-6B -acetylthio-l7u-ethyny1-5a-estran-3-one, is prepared from 5a,6a-epoxy-l7a-ethynyl-5a-estrane 3fi,17B-dio1 [Ringold et al.: J. Am. Chem. Soc., Vol. 81, p. 436 (1959)] by treatment with thiolacetic acid at room temperature, followed by oxidation with chromium trioxide in acetone in the presence of sulfuric acid.

EXAMPLE 15 EXAMPLE 16 To a solution of fi-bromol 7B-acety1oxy-4-androsten-3one (2.24 g.) in acetone (60 ml.), there is added potassium thiolacetate (1.26 g.), and the resultant mixture is stirred for 4 hours at room temperature (10 to 30 C.). The reaction mixture is combined with water and shaken with a mixture of ether and chloroform (4:1). The organic solvent layer is separated, washed with dilute sodium carbonate solution and water in order, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from a mixture of ether and petroleum ether to give 6a-acetylthio-17B-acetyloxy-4- androsten-3-one (1.37 g.) as crystals melting at 192 to 194 C. The mother liquor of crystallization is purified by chromatography on activated magnesium silicate to give additional crystals (0.27 g.) of the same substance.

The starting materials of this example, 6B-bromo-17B- acety1oxy-4-androsten-3-one, is prepared from testosterone acetate by treatment with N-bromosuccinimide in carbon tetrachloride.

EXAMPLE 17 To a solution of 6B-bromo-17B-propiony1oxy-4-androsten-3 -one (0.93 g.) in dimethylforrnamide (20 ml.), there is added potassium thiolacetate (0.80 g.), and the resultant mixture is stirred for 30 minutes at room temperature (10 to 30 C.). The reaction mixture is combined with water and shaken with a mixture of ether and dichloromethane (4:1). The organic solvent layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from a mixture of ether and petroleum ether and recrystallized from methanol to give 6a-acetylthio-17B-propionyloxy-4-androsten-3-one (0.71 g.) as crystals melting at 151 to 153 C. [621,5 40.9 i 2 1.006, chloroform). UV-Spectrum: xgggg 235.5 mu (6 16,200). lR-Spectrum: 11. 52 39 1,731, 1,696, 1,675, 1,610, 1,190, 1,130 C111,. Anal. Calcd. for C ,H O S: C, 68.86; H,-8.l9; S, 7.66. Found: C, 68.71; H, 8.21; S, 7.79.

The starting material of this example is prepared from testosterone propionate by bromination with N-bromosuccinimide.

EXAMPLE 18 To a solution of 6/3-bromo-17B-acetyloxy-4-estren-3-one (1.14 g.) in acetone (40 ml.), there is added potassium thiolacetate (0.67 g. and the resultant mixture is stirred for 4 hours at room temperature 10 to 30 C.). The reaction mixture is combined with water and shaken with ether. The ether layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on activated magnesium silicate. The fraction eluted with benzene-ether (9: 1-1:1 is concentrated to give 6B-acetylthio- 17B-acetyloxy-4-estren-3-one(1.00 g.) as an oil. lR-Spectrum: 1,746, 1,696(shoulder), 1,688, 1,626, 1,138, 1,250 cm".

The starting material of this example, 6B-bromo-17B- acetyloxy-4-estren-3-one, is prepared from 3,17-cliacetyloxy- 3,5-estradiene [Velluz et al.: French Pat. No. 1,180,907] by treatment with N-bromoacetamide and sodium acetate in refluxing acetic acid.

EXAMPLE 19 To a solution of 6fl-bromo-17B-acetyloxy-l 7a-etl1yny1-4estren-3-one (0.80 g.) in acetone (30 ml.), there is added potassium thiolacetate (0.78 g.), and the resultant mixture is allowed to stand at room temperature (10 to 30 C.) for 2.5 hours. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dried and concentrated. The residue is crystallized from ether to give crystals (0.34 g.). The mother liquor of crystallization is concentrated and chromatographed on activated magnesium silicate. The fraction eluted with etherbenzene is concentrated and crystallized from a mixture of acetone and hexane to give 6a-acetylthio-l7B-acetyloxy-l7aethynyl-4-estren-3-one (0.42 g.) as crystals melting at 216 to 219 c.(decomp.). [a] '-34.4fl (c=0.999, chloroform). UV-Spectrum: xggp 235.5 mp. (517,343). lR-Spectrum: pgg 3,300, 1,742, 1,690(shou1der), 1,674, 1,623, 1,260, 1,134, 1,120, 1,022 cm. Anal. Calcd. for C l-1 0 8: C, 69.53; 1 1, 7.29; S, 7.74. Found: C, 69.54; H, 7.35; s, 7.86.

EXAMPLE 20 To a solution of 6B-bromo-17B-hydroxy-l7a-ethynyl-4-es tren-3-one (4.57 g.) in acetone (70 ml.), there is added potassium thiolacetate (2.80 g.), and the resultant mixture is stirred for 3 hours at room temperature 10 to 30 C. The reaction mixture is combined with water and shaken with ether. The ether layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated to give 6aacetylthio- 1 7fl-hydroxy-17a-ethyny1-4-estren-3-one l .44 g. as an oil. lR-Spectrum: 3; 3,626, 3,286, 1,700, 1,687,

The starting material of this example, 6B-bromo-17B- hydroxy-l7a-ethyny1-4'estren-3-one, is prepared from 3- ethoxy-17/3-hydroxy-l7a-ethynyl-3,5-estradiene [Knox et al.: J. Am. Chem. Soc., Vol. 82, p. 1,230 (1960)] by treatment with N-bromosuccinimide in acetone in the presence of sodium acetate.

EXAMPLE 21 EXAMPLE 22 To a solution of 6B-bromo-17,20:20,2 l-bismethylenedioxy- 4-pregnene-3,1l-dione (3.42 g.) in dimethylformamide (40 ml.), there is added potassium thiolacetate (1.62 g.), and the resultant mixture is stirred at room temperature (10 to 30 C.) for 5 hours. Reaction mixture is combined with water. The precipitate is collected by filtration, crystallized from a mixture of acetone and hexene and recrystallized from a mixture of dichloromethane and methanol to give 6a-acetylthiol7,20:20,2 l -bismethylenedioxy-4-pregnene-3 ,1 l-dione (2.43 g.) as crystals melting at 234 to 236 c. a '+140.3:2 0:11.965, chloroform). lR-Spectrum: M mi- 9' 1. 1,675,1,609,1,l35,1,098,1,081cm.".

lclaim:

1. A compound of the formula S-Ac wherein Ac is a lower alkanoyl group, R is hydrogen or methyl, R is a hydroxy, O-Ac, acetyl, hydroxyacetyl or a 17- side chain of the cholestane series, R is hydrogen, hydroxy, lower alkyl, lower alkenyl or lower alkynyl, or when combined together R and R represent an oxygen atom or a group of the formula inn t) Z is methylene or carbonyl, and the mark 2 represents either the a or B-configuration.

2. A compound according to claim 1, wherein R is methyl, R and R combined together represent oxo, Z is methylene and Ac is acetyl.

3. A compound according to claim 1, wherein R, is methyl, R is hydroxy or lower alkanoyloxy, R is hydrogen, Z is methylene and Ac is acetyl.

4. A compound according to claim 1, wherein R is methyl, R, is acctyl, R is hydrogen, hydroxy or acyloxy, Z is methylene and Ac is acetyl.

5. A compound according to claim 1, wherein R, is methyl, R, and R combined together represent a group of the formula partial formula wherein Ac is a lower alkanoyl group and the mark i represents either the a or B-configuration, with a dehydrating agent.

9. A process for preparing a compound as claimed in claim 1, which comprises reacting a steroid compound having the partial formula S Ac wherein X is a halogen atom and the mark E represents either the a or B-configuration, with a salt of a thiol-lower alkanoic acid.

10. A process for preparing a compound as claimed in claim 1, namely a compound having the partial formula 2 X wherein Ac is a lower alkanoyl group, which comprises reacting a compound having the partial formula wherein Ac is defined as above, with an organic or inorganic acid.

1 1. A process according to claim 8 wherein the dehydrating agent is an acid or an inorganic ogtyacid halide.

12. A process according to claim 8 wherem the dehydrating 

2. A compound according to claim 1, wherein R1 is methyl, R2 and R3 combined together represent oxo, Z is methylene and Ac is acetyl.
 3. A compound according to claim 1, wherein R1 is methyl, R2 is hydroxy or lower alkanoyloxy, R3 is hydrogen, Z is methylene and Ac is acetyl.
 4. A compound according to claim 1, wherein R1 is methyl, R2 is acetyl, R3 is hydrogen, hydroxy or acyloxy, Z is methylene and Ac is acetyl.
 5. A compound according to claim 1, wherein R1 is methyl, R2 and R3 combined together represent a group of the formula Z is carbonyl or methylene and Ac is acetyl.
 6. A compound according to claim 1, wherein R1 is hydrogen, R2 is hydroxy or lower alkanoyloxy, R3 is hydrogen or ethynyl, Z is methylene and Ac is acetyl.
 7. A compound according to claim 1, wherein R1 is methyl, R2 is the cholestane side chain, R3 is hydrogen, Z is methylene and Ac is acetyl.
 8. A process for preparing a compound as claimed in claim 1, which comprises reacting a steroid compound having the partial formula wherein Ac is a lower alkanoyl group and the mark represents either the Alpha or Beta -configuration, with a dehydrating agent.
 9. A process for preparing a compound as claimed in claim 1, which comprises reacting a steroid compound having the partial formula wherein X is a halogen atom and the mark represents either the Alpha or Beta -configuration, with a salt of a thiol-lower alkanoic acid.
 10. A process for preparing a compound as claimed in claim 1, namely a compound having the partial formula wherein Ac is a lower alkanoyl group, which comprises reacting a compound having the partial formula wherein Ac is defined as above, with an organic or inorganic acid.
 11. A process according to claim 8 wherein the dehydrating agent is an acid or an inorganic oxyacid halide.
 12. A process according to claim 8 wherein the dehydrating agent is thionyl chloride in pyridine.
 13. A process according to claim 8 wherein the dehYdrating agent is hydrogen chloride in acetic acid.
 14. A process according to claim 9, wherein the salt of a thiol-lower alkanoic acid is potassium thiolacetate in acetone or dimethylformamide.
 15. A process according to claim 10, wherein the organic or inorganic acid is selected from hydrochloric acid and p-toluenesulfonic acid. 